Neovascularization, or the formation of new blood vessels, is a highly complex and tightly regulated biological process. Neovascularization begins with the enzymatic breakdown of the basement membrane of a blood vessel. Endothelial cells migrate through the area of degradation, invade the surrounding extracellular matrix, and proliferate to form an elongated column of cells. A lumen forms within the solid cell column upon differentiation of endothelial cells and the basement membrane is subsequently regenerated. Eventually, the newly formed vessel structure connects with existing blood vessels (see, for example, Fotsis et al., 1995. J. Nutr., 125: 790S-797S). The newly formed vessel, as well as existing vessels, can further divide to form branches and capillary networks. The division of existing vessels to form capillary networks is called non-sprouting angiogenesis or intussusception.
Neovascularization is not continuously required on a large scale in adult animals. Indeed, the process for forming blood vessels is often quiescent except in instances of injury and wound repair. Neovascularization is controlled, at least in part, by the body's requirement for a precise combination of signaling molecules, chemical messengers, and mechanical signals to coordinate the biological events necessary for functional blood vessel formation. When vascularization is not stringently controlled, serious pathologies can result. Uncontrolled vascularization is associated with, for instance, tumor growth, edema, diseases of eye (e.g., diabetic retinopathy and the exudative form of age-related macular degeneration), rheumatoid arthritis, psoriasis, and atherosclerosis.
Several strategies for controlling vascularization have been proposed, and many angiogenesis inhibitors have been identified including angiostatin, endostatin, pigment epithelium-derived factor (PEDF), and protamine. However, a major hurdle in treating or preventing angiogenesis is targeting processes uniquely associated with unwanted neovascularization to avoid side effects. For example, U.S. Pat. No. 6,833,373 proposes administering an “integrin antagonist” to, e.g., impair endothelial cell adhesion via integrins, thereby prompting cell death of proliferating endothelial cells. Bouroulous et al. (J. Cell Biol., 143(1): 267-276 (1998)) reported that a 76 amino acid III1-C fibronectin fragment, which forms one of fibronectin's self-assembly sites, causes disassembly of fibronectin matrix and inhibited cell migration and proliferation. However, subsequent studies established that the III1-C fibronectin fragment (also known as “anastellin”) did not act by reducing the level of fibronectin present in the extracellular matrix (see, e.g., Ambesi et al. 2005. Cancer Res., 65(1): 148-156). Instead, it has been proposed that anastellin works through a different mechanism, which may include integrin binding (Ambesi, supra). However, integrins are found on many cell types other than endothelial cells, and play a role in other vital physiological processes that would be disrupted by inhibiting integrin function.
Thus, there exists a need for a means of specifically inhibiting vascularization in an animal.